Rocca et al. BMC Medical Genetics(2020) 21:220
https://doi.org/10.1186/s12881-020-01160-5

CASE REPORTOpen Access

A novel genetic variant in DNAI2 detectedby custom gene panel in a newborn withPrimary Ciliary Dyskinesia: case report
Maria Santa Rocca1, Gioia Piatti2, Angela Michelucci3, Raffaella Guazzo4, Veronica Bertini5, Cinzia Vinanzi1,
Maria Adelaide Caligo3, Angelo Valetto5 and Carlo Foresta1*

Abstract
Background: Primary ciliary dyskinesia (PCD) is a highly heterogeneous genetic disorder caused by defects inmotile cilia. The hallmark features of PCD are the chronic infections of the respiratory tract, moreover, clinicalmanifestations include also laterality defects and risk of male infertility.
Clinical phenotypes of PCD are the result of mutations in genes encoding components of axonema or factors
involved in axonemal assembly. Recent studies have identified over 45 PCD-associated genes, therefore, molecularanalysis represents a powerful diagnostic tool to confirm and uncover new genetic causes of this rare disease.
Case presentation: Here, we describe a female infant of Moroccan origin with normal pressure hydrocephalus(NPH) in addition to most common PCD symptoms. Transmission Electron Microscopy (TEM) and molecular tests,
such as a Next generation Sequencing panel and a custom array CGH, were performed for diagnosis of PCD. TEM
revealed outer dynein arm (ODA) defects, whilst molecular analyses detected a novel 6,9 kb microdeletion in DNAI2
gene.
Conclusions: Since DNAI2 mutations are very rare, this case report contributes to better delineate the importantrole of DNAI2 as causative of PCD phenotype, suggesting, furthermore, that the variations in DNAI2 may be as a
new genetic risk factor for NPH. Indeed, although the association of hydrocephalus with PCD has been well
documented, however, only a small number of human patients show this defect.
Furthermore, this study highlights the importance of high-throughput technologies in advancing ourunderstanding of heterogeneous genetic disorders.
Keywords: Primary ciliary dyskinesia, DNAI2, Outer dynein arm, PCD genetic panel, Normal pressure hydrocephalus

BackgroundPrimary ciliary dyskinesia (PCD) (MIM: 244400) is a rare
heterogeneous disorder caused by dysfunction of motile
cilia, resulting in recurrent respiratory infections due toimpaired mucociliary clearance. The disease is predominantly caused by mutations in genes encoding for the* Correspondence: carlo.foresta@unipd.it
1
Department of Medicine, University of Padova, Via Giustiniani, 2, 35128
Padova, Italy
Full list of author information is available at the end of the article

ciliary axonemal motor proteins that regulate ciliarybeat.
PCD is mainly transmitted in an autosomal recessive pattern and has a prevalence of 1 in 10,000–20,000 individuals [24]. Typical clinical manifestations of
this disorder include neonatal respiratory distress,
chronic rhinosinusitis, hearing impairment, development of bronchiectasis, male infertility and situs
abnormalities (predominantly situs inversus, rarely
situs ambiguous) occurring in about 50% of cases.

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Rocca et al. BMC Medical Genetics(2020) 21:220

However, less common clinical manifestations havebeen also described in PCD patients, such as
oesophageal disease, biliary atresia, complex congenital heart disease and hydrocephalus [2, 6, 19].
Since many symptoms of PCD can overlap with othermost common respiratory diseases, this leads to an underestimation of the real prevalence of this disorder [3, 31].
Furthermore, since PCD lacks of a “gold standard”
test the diagnosis is usually based on a combinationof tests: nasal nitric oxide (nNO) measurement, highspeed video microscopy analysis (HSVMA), TEM andgenetic tests [30].
The heterogeneity of the clinical presentations in PCD
patients reflects the genetic heterogeneity of this disorder; moreover, heterogeneity may also exist even between patients with the same genetic defect [34]. To
date, indeed, mutations in approximately 45 genes havebeen linked to PCD [9, 35] and genetic test is currently
able to identify 70–80% of PCD cases [7].
To establish the genetic diagnosis, non-ambiguous biallelic mutations in autosomal recessive PCD should be
identified [22]. Among all genetic mutations, nearly 15–
20% of all PCD patients results from mutations within
Dynein Axonemal Heavy Chain 5 (DNAH5) gene (MIM:
603335) [10, 27] causing outer dynein arm (ODA) defects [14]; DNAH5 and Dynein Axonemal Intermediate
Chain 1 (DNAI1) mutations are the most frequent mutations encountered in correlation with ODA defects, ~50% and ~ 10% of cases, respectively [23]; mutations inother genes are much less frequent.
Dynein Axonemal Intermediate Chain 2 (DNAI2) is acomponent of ODA complex and is essential for the assembly of this multimeric complex. The protein is
encoded by DNAI2 gene (MIM: 605483) consisting of 14exons and mapping to 17q25; mutations in DNAI2 geneare a rare cause of PCD with associated ODA defects at
ciliary ultrastructure analysis (2–4%) [21].
Here, we describe the case of a four-month-old female
infant carrying a novel homozygous deletion in DNAI2,
and hypothesize that the typical signs of PCD of this patient, in addition to a rare clinical manifestation associated to PCD such as hydrocephalus, are the result of theidentified genetic variation. Furthermore, we support theapplication of high-throughput molecular techniques forthe analysis of patients affected by this rare disorder.

Case presentation
Clinical characteristics

The patient was a female second-born child of healthy
non-consanguineous Moroccan parents with an unremarkable family history.
Foetal ultrasonography (US) performed at the second
trimester of gestation showed brain ventriculomegaly
and situs inversus. The proband was born by

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spontaneous delivery at 41 week of gestation. The day
after the birth, she showed a mild polypnoea requiring
oxygen supplementation because of a low HbO2 saturation (< 90%). At third day of age, the newborn showedstable cardiorespiratory parameters and oxygen was discontinued after one week; no ventilatory support was necessary. A lobar collapse was observed on chest X-ray.
Antibiotic therapy was requested to reduce the respiratory inflammation pointed out from high CRP (CReactive Protein) and white blood cell (WBC) countvalues, but microbiological tests on blood and tracheal
aspirate resulted negative. The patient remained hospitalized for two weeks and dismissed from hospital withdiagnosis of brain ventriculomegaly, situs inversus andpatency of foramen ovale.
A brain MRI carried out on the fifth day of life detected an enlargement of III ventricle and lateral ventricles and NPH. Severe enlargement of lateral ventricles
was confirmed with echography at the second month ofage. The patient was followed-up during the first monthsof life and only monitored with echography and by
neurological visits, including monitoring of head circumference measure. The neurological examination at third
month of life found a girl reactive, without asymmetries,
with good control of the head and who began to control
the trunk. A lumbar puncture was not performed; nosurgical treatment for hydrocephalus were carried out.
Observational examination at fourth month of age did
not reveal neurological anomalies.
A karyotype analysis was performed revealing a normal female karyotype (46,XX).
Diagnostic tests

The study of ciliary motility performed at third monthof age did not identify ciliated cells suitable for analysis
of ciliary beat frequency and pattern, but showed exclusively inflammatory cells and many bacteria.
Ciliary brushing biopsy was taken from the nasal middle turbinate for ciliary ultrastructure analysis.
At least 50 cross section of cilia from different cells
were observed for ultrastructural analysis.
Genetic testing

DNA was isolated from peripheral blood leukocytes using
QIAamp DNA Blood Mini Kit (Qiagen Inc., Hilden,
Germany) for molecular analysis. We carried out a custom
Next Generation Sequencing (NGS) using a panel including the coding exons and flanking regions of 36 genes
known to be involved in PCD (Additional file 1) and sequenced on a MiSeq sequencer (Illumina, San Diego, CA,
USA). Read alignment to reference genome (hg19), variant
calling and annotation were performed with the Agilent
SureCall software. The list of putative variants obtained
were SNVs and small insertions and deletions with respectRocca et al. BMC Medical Genetics(2020) 21:220

to a reference genome. Finally, the sequencing coverage ofeach exons was analysed in detail using IGV (Integrative
Genomic Viewer) visualization tool.
For array Comparative Genomic Hybridization (aCGH)
analysis, 200 ng of DNA from the patient (test sample) anda human reference female DNA (cat 5190–3797) of Agilent
kit were differentially labelled with Cy5-dCTP or with Cy3dCTP using random primer labelling according to manufacturer’s protocol (Agilent). The array CGH was performed on a customized 60 K SurePrintG3 Human CGH
Microarray (Agilent), enriched in the genes included in
NGS panel. The slide were washed and scanned using theAgilent scanner and the identification of individual spots
on scanned arrays and quality slide evaluation was performed with the Agilent dedicated software (Feature Extraction, Agilent). For these genes, the overall medianprobe spacing is about 1.8 Kb. Copy Number Variations
were identified with Cytogenomics 3.0.6.6. (Agilent), using
the ADM-2 (Aberration Detection Method-2) algorithm.
We analysed all the CNVs, independently of their absolutesize; they were compared to those reported in the http://
dgv.tcag.ca/variation.
TEM highlighted the absence or shortened outer arm
dyneins in 100% of analysed cells (Fig. 1).
Sequencing by NGS panel identified a homozygous deletion of 7–9 exons in DNAI2 gene (chr17: 72.295.857–
72.301.581; hg19). The deletion was confirmed by custom aCGH that detected a 6,9 kb homozygous deletionin DNAI2 gene, starting from position 72.295.232 toposition 72.302.209 (GRCh37/hg19) in 17q25.1: arr
17q25.1(72.295.232–72.302.209) × 1 (Fig. 2).
Unfortunately, the unavailability of both parental DNA
did not allow us to determine inheritance pattern of theidentified deletion.

Discussion and conclusions
PCD is a rare genetically disorder characterized by chronic
respiratory disease, infertility and situs anomalies

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occurring in about 50% of cases as result of defective motile cilia. Cilia are specialized organelles that extend fromthe cellular surface of respiratory epithelium, ependymal
cells, gonads and embryonic node [35]. Mutations in any
protein involved in cilia assembly, structure or function
could cause disease and to date a considerable number ofgenes have been implicated in this disorder [9].
Diagnosis of PCD is often delayed or missed completely, especially when organs symmetry is correct. An
European survey on paediatric cases showed a medianage of diagnosis of 5.3 years, lower in children with situs
inversus (3.5 years vs 5.8 years) [18].
Under-diagnosis or late-diagnosis of PCD likely could
contribute to increase the risk of a progressive decline inlung function in these patients [26].
Although the assessment of ciliary ultrastructure by
TEM was previously considered the gold standard for
PCD diagnosis [17], it is known that up to 30% of PCD
cases can have a normal ciliary structure appearance[16], since they have mutations that are not associatedwith ultrastructural defects [4, 22]. Therefore, over lastyears, advances in genetic testing and molecular biology,
have improved knowledge on this hereditary rare disease. The molecular analysis, in combination with otherdiagnostic tests, such as ultrastructural microscopy,
high-speed video microscopy and nNO determination,
represents, hence, an important diagnostic tool to confirm PCD [20].
Furthermore, based on the large number of PCDcausing genes, it has become evident that the applicationof new high-throughput technologies can simplify the
genotype-phenotype correlation and complement ciliary
analysis [13]. To date, mutations in over 45 genes havebeen identified as causative of PCD [9]. Such mutations
are in genes encoding axonemal motor proteins, structural and regulatory elements, and cytoplasmic proteins,that are proteins involved in assembly and pre-assemblyof ciliary elements [8]. However, the identification of bi-

Fig. 1 a Ultrastructure of a normal cilium from nasal epithelium of a healthy subject showing nine peripheral pairs of microtubules with outerand inner dynein arms clearly visible (100.000 x). b Representative transmission electron micrograph of a cross-sectioned cilium from the patientdemonstrating the absence of outer dynein arms (100.000x)

Rocca et al. BMC Medical Genetics(2020) 21:220

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Fig. 2 Chromosome 17 array profile (left); highlight of the homozygous deleted region, involving the DNAI2 gene (right)

allelic pathogenic variants in known PCD-associatedgenes should be enough to give a diagnosis of PCD [9].
In the present study, we report the case of a fourmonth-old female infant carrying a novel homozygous
deletion within DNAI2 gene detected by NGS sequencing and confirmed by custom aCGH.
DNAI2 is a member of the ODA complex and its gene,
DNAI2, results mutated in approximately 2 to 4% of
patients with PCD [13, 14, 21].
To best our acknowledgement, few mutations in
DNAI2 gene have been described, supporting the hypothesis of an evolutionarily conserved functional rolefor DNAI2 in ODA assembly [21].
Our case adds further information to PCD disease as
result of alterations in DNAI2, corroborating the fundamental role of DNAI2 protein.
Interestingly, since the proband shows a less common
clinical sign of PCD, such as hydrocephalus, in addition
to the typical symptoms, our finding could add significant insights into genetic causes of hydrocephalus.
Hydrocephalus is a common disorder of cerebral spinal
fluid that has been widely reported in animal models
with PCD, mainly in mouse [19], indeed, it has been
showed that Mdnah5-deficient mice develop severehydrocephalus at early postnatal ages, that is associatedwith ultrastructural axonemal defects within the ODA[11] and altered motility of ependymal cilia, so indicating
a clear link between hydrocephalus formation and cilia
dysfunction. On the contrary, there are few reports
reporting hydrocephalus as clinical manifestation in human PCD subjects: the low prevalence of hydrocephalus
in PCD patients suggests that distinct genetic mechanisms involved in the development and physiology ofhuman and mouse brains are different. In literature,hydrocephalus has never been reported linked to DNAI2
mutations, that is the novel finding here reported. In a
few PCD cases described with hydrocephalus, ODA absence was the most frequent ultrastructural alteration
observed [5, 32], even if some authors have also reported
IDA
defects,
sometimes
accompaniedbyadisorganization of the central-pair microtubules [1, 15,
28, 33]. In our case, a ODA absence or shortening in
100% of the ciliary cross-sections was detected by theelectron microscopic examination and this result is consistent with an isolated ODA defect, in agreement withthe genetic results.
However, the observation of NPH in this patient results very intriguing. NPH is a form of hydrocephalus
characterized by ventricular enlargement and normal
cerebrospinal fluid pressure. The aetiology of NPH is
unknown and, to date, the genetic origin has been supposed in a few cases [12, 25, 29]. Therefore, the novel
DNAI2 microdeletion detected in our patient could suggest the potential implication of this genetic variant in
the pathogenesis of NPH offering new insight on thegenetic factors that could play a key role in the pathogenesis of NPH. Indeed, the mutations that compromise
the function of motile cilia could be likely causative of
the abnormalities in the flow of cerebrospinal fluid.
A major limitation of our case report is the lack of an
expression assays or functional analysis; missing
HSVMA study and nNO results are another limitation.
In conclusion, this study emphasizes further the important function of DNAI2, suggesting the alteration of
DNAI2 protein as causative of PCD and as genetic risk
factor of NPH. Furthermore, the study underlines theutility of application of new high-throughput technologies in order to get an early genetic diagnosis.

Rocca et al. BMC Medical Genetics(2020) 21:220

However, although the clinical manifestations of ourpatient suggest a likewise loss of function of DNAI2 protein, functional studies and immunofluorescence analyses are to be performed in order to better delineate theeffect of the detected DNAI2 deletion on ciliary
ultrastructure.

Supplementary Information

Page 5 of 6

2.

3.

4.

The online version contains supplementary material available at https://doi.
org/10.1186/s12881-020-01160-5.
5.
Additional file 1. 36 genes include in PCD panel.
6.
Abbreviations
PCD: Primary ciliary dyskinesia; NPH: Normal Pressure Hydrocephalus;
TEM: Transmission electron microscopy; nNO: Nasal nitric oxide;
HSVMA: High-speed video microscopy analysis; DNAH5: Dynein Axonemal
Heavy Chain 5; DNAI1: Dynein Axonemal Intermediate Chain 1;
DNAI2: Dynein Axonemal Intermediate Chain 2; FUS: Foetal ultrasonography;
CRP: C-Reactive Protein; WBC: White blood cell; NGS: Next Generation
Sequencing; aCGH: Array Comparative Genomic Hybridization; ODA: Outerdynein arm
Acknowledgements
Not Applicable.
Authors’ contributions
MSR designed the study, interpreted results, and wrote the manuscript. GP
performed clinical analysis. RG performed TEM analysis. AM performed NGS
sequencing. VB and AV performed a-CGH analysis. CV and MAC have revisedmanuscript critically. CF supervised the project and critically reviewed study.
All authors provided feedback and contributed to the final version of themanuscript.

7.

8.

9.

10.

Funding
No funding.
11.
Availability of data and materials
The reference sequence for validation of the deletion in the DNAI2 gene was
acquired from the NCBI Nucleotide database by using accession number
NM_023036.6. The raw sequencing data is available in NCBI’s BioProject
under the accession number SRR12830850, BioProject: PRJNA669228 (https://
dataview.ncbi.nlm.nih.gov/object/SRR12830850)].

12.
13.

Ethics approval and consent to participate
This study was approved by the Ethics Committee of the University Hospitalof Padova. A written informed consent was obtained from parents.
Consent for publication: A written informed consent to publication has beenobtained from the parents.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Department of Medicine, University of Padova, Via Giustiniani, 2, 35128
Padova, Italy. 2Unit of Bronchopneumology, Department of Pathophysiology
and Transplantation, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore
Policlinico, University of Milan, Milan, Italy. 3Laboratory of Molecular Genetics,
University Hospital of Pisa, Pisa, Italy. 4Unit of Pathological Anatomy,
Department of Medical Biotechnology, University of Siena, Siena, Italy.
5
Laboratory of Cytogenetics, University Hospital of Pisa, Pisa, Italy.
Received: 20 July 2020 Accepted: 28 October 2020

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